Although there has been much progress in understanding the early phases of capillary formation (protease production, proliferation and migration), very little is known about the later events including the association of pericytes with capillaries and the remodeling of primordial capillaries into larger caliber vessels. Experimental observations both in vivo and in vitro indicate that vascular morphogenesis is likely to be a complex process, involving soluble factors and cell-cell interactions, as well as exogenous forces. Developmental studies suggest that endothelial cells (EC) are capable of recruiting mural cells and subsequently influencing their growth and behavior. We propose to examine this possibility by systematically assessing the effects of EC on mural cell growth and migration. It is well-documented that placement of a vein segment into the arterial circulation results in "arteriolization" characterized by SMC proliferation and connective tissue synthesis. This phenomenon strongly points to a role for mechanical stretch in the regulation of smooth muscle cell (SMC) growth and function. To assess the role that stretch might play in vascular morphogenesis, we propose to use both in vivo and in vitro models to examine the effects of mechanical stretch on the proliferation of vascular EC and mural cells and their expression of relevant growth factors. The ratio of the number of EC lining the intimal surface to layers of mural cells appears to be finely controlled throughout the vascular system. There are, however, vascular anomalies including vascular malformations and hemangiomas, characterized by inappropriate EC:SMC ratios (e.g. a paucity of mural cells). Investigation of EC-mural cell interactions using EC derived from these abnormal vessels may provide insight into the mechanisms that underlie normal vascular morphogenesis. Thus, we propose to compare normal and transformed EC for their ability to produce and respond to vascular growth factors, interact with mural cells, and respond to exogenous stretch. Results of these studies should allow us to begin to define the events involved in the later stages of capillary assembly and in the morphogenic processes involved in large blood vessel formation as well as the mechanisms which underlie vascular cell behavior in injury and in pathology.